OVERALL SUMMARY The main focus of this Program Project Grant is to discover the foundational and translational knowledge needed to create an office-based handheld ultrasound device to target, detach, break, and expel stones and stone fragments from the urinary space to facilitate natural clearance. This system will obviate costly and inefficient emergency department visits that typically include repetitive exposure to ionizing radiation from diagnostic imaging, and will significantly reduce the often lengthy (days to weeks) wait time patients must endure before procedures for stone removal can be scheduled and performed. As the proposed therapy system is entirely noninvasive, patients will be treated on an outpatient basis. Further, as the system is designed to efficiently and painlessly break stones of any size and expel the fragments from the kidney, the treatment of both symptomatic and asymptomatic stones using this technology will reduce the high retreatment and stone event recurrence rates associated with current surgical interventions for stone removal. In this effort, we will combine stone breakage by burst wave lithotripsy (BWL), clearance of fragments by ultrasonic propulsion (UP), and stone-specific ultrasound imaging (S-mode) into an integrated system in which exposure strategies are adapted during treatment in response to real-time acoustic feedback to enhance comminution efficiency and patient safety. We will tailor treatment by investigating numerically and in lab tests the primary mechanisms - cavitation and elastic waves - involved in the comminution process over a broad parameter space. We will develop acoustics-based feedback including model- based, machine learning and passive acoustic mapping (PAM) of the bubble field to signal the need to adjust the energy output. We will investigate the morphological and functional response of the kidney in living animals and in ex vivo perfused porcine kidneys, and pursue tissue protective treatment strategies such as power ramping. These studies will include the first in-human test of BWL in which we will compare the comminution effectiveness and safety of treatment with and without adaptive output control in response to acoustic feedback. In addition, we will conduct a randomized controlled trial of the benefits and risks of fragmenting and expelling symptomatic and asymptomatic stones in the clinic. Toward application of the system for use in humans, we will refine and validate the use of UP and S-mode together to improve stone and fragment detection. With our eye on the future of stone management, we will develop and validate in vivo an extracorporeal acoustic tractor beam to grasp and carry fragments through the complex three- dimensional path of the urinary space and out of the kidney.